Primary biliary cirrhosis (PBC) is a disease of unknown etiology characterized by slowly progressive intrahepatic cholestasis due to non-suppurative presumably autoimmune destruction of septal and the larger interlobular bile ducts. In controlled trials neither penicillamine nor azathioprine have unequivocally improved survival or slowed the progression of the disease. Because certain other autoimmune diseases appear to respond favorably to alkylating agents but not to azathioprine, a controlled trial of chlorambucil therapy for patients with PBC has been initiated. Twenty-four patients (23 women, 1 man; age 34-63) have been admitted to this trial: 13 were randomized to chlorambucil therapy and 11 to the control group. All patients have been followed for at least two years and some for as long as five years. Two of the patients in the control group but none of the treated patients have died. Serum bilirubin levels have remained stable in treated patients, but have remained markedly elevated in most of the untreated patients. IgM levels have decreased significantly in the treated patients but have risen in the untreated patients. Liver biopsies have revealed a marked diminution in hepatic inflammation among the treated patients.